Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice

Abstract

Anxiety-associated symptoms following acute stress usually become extinct gradually within a period of time. However, the mechanisms underlying how individuals cope with stress to achieve the extinction of anxiety are not clear. Here we show that acute restraint stress causes an increase in the activity of GABAergic neurons in the CeA (GABACeA) in male mice, resulting in anxiety-like behaviors within 12 hours; meanwhile, elevated GABACeA neuronal CX3CL1 secretion via MST4 (mammalian sterile-20-like kinase 4)-NF-κB-CX3CL1 signaling consequently activates microglia in the CeA. Activated microglia in turn inhibit GABACeA neuronal activity via the engulfment of their dendritic spines, ultimately leading to the extinction of anxiety-like behaviors induced by restraint stress. These findings reveal a dynamic molecular and cellular mechanism in which microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress.

Long-term intake of thermo-induced oxidized oil results in anxiety-like and depression-like behaviors: involvement of microglia and astrocytes

“…Some researchers have found through immunofluorescence experiments that the number of microglia increases and is activated when anxiety is generated. 8 Numerous articles have documented the close interaction between microglia and astrocytes. 62 Specifically, it has been observed that an increase in M1 microglia leads to the production of pro-inflammatory factors by astrocytes, whereas an increase in M2 microglia prompts astrocytes to produce anti-inflammatory factors.…”

“…7 In 2024, a new study found that microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress. 8 And other studies have found that abnormal cortical excitability, atypical excitatory neurotransmission and increased levels of metabolites are significantly associated with anxiety and depression. 9,10…”

Stress-induced anxiety-related behavior in mice is driven by enhanced excitability of ventral tegmental area GABA neurons

“…The occurrence of post-traumatic stress disorder (PTSD) following a single traumatic event highlights the potent influence of stress in the etiology of clinically relevant anxiety ( Yehuda et al, 2015 ). Acute stress exposure in mice is sufficient to induce anxiety symptomatology via several modalities, including restraint ( Kemp et al, 2022 ; Liu et al, 2023 ; Chen et al, 2024 ) and inescapable shock ( Tillage et al, 2020 , 2021 ; McGovern et al, 2022 ). The effect of acute stress also translates to humans ( Grillon et al, 2007 ; Daviu et al, 2019 ).…”